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Essentials of Glycobiology April 4, 2000 Jeff Esko

Essentials of Glycobiology April 4, 2000 Jeff Esko. Lecture 1 Course Overview & General Introduction. Lecture 1 - Key Points. What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together

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Essentials of Glycobiology April 4, 2000 Jeff Esko

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  1. Essentials of GlycobiologyApril 4, 2000Jeff Esko Lecture 1 Course Overview & General Introduction

  2. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  3. What is Glycobiology? In its simplest form, glycobiology is the study of the structure, chemistry, biosynthesis, and biological functions of glycans and their derivatives. Glycobiology is an integrative science, crossing all subfields of chemistry, biology and medicine. Chemical analysis and biochemistry dominated the field in the early part of the century. In the 1960’s, glycans in the extracellular matrix, on the cell surface, and in the interior of cells were found to have biological properties independent of the underlying protein or lipid. The term “glycobiology” was coined in 1988 by Rademacher, Parekh, and Dwek: Annu Rev Biochem. 57:785-838.

  4. Macromolecules DNA æ RNA æ Protein æ Cell æ Organism

  5. Carbohydrates Cells Glycoconjugates Organisms Lipids Revised Paradigm DNA RNA Protein Enzymes

  6. All cells are covered by a glycocalyx, a meshwork of complex carbohydrates Glycocalyx EM of endothelial cells from a blood capillary showing the lumenal plasmalemma decorated with particles of cationized ferritin (courtesy of George E. Palade, UCSD).

  7. Proteoglycans Glycolipids Glycoproteins Cytoplasmic Glycosylation

  8. Central Dogma • Glycans occur in patterns that are characteristic of the cell, tissue and organism • Patterning is not template driven • Glycan composition and pattern depends on enzyme expression (transferases), substrate specificity, and the availability of precursors

  9. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  10. Basic Definitions • Carbohydrate, glycan, saccharide, sugar: Generic terms used interchangeably. Includes monosaccharides, oligosaccharides, polysaccharides, and derivatives of these compounds. Carbohydrates consist of “hydrated carbon”, [CH2O]n • Monosaccharide: A carbohydrate that cannot be hydrolyzed into a simpler carbohydrate. The building block of oligosaccharides and polysaccharides. • Oligosaccharide: Linear or branched chain of monosaccharides attached to one another via glycosidic linkages. The number of monosaccharide units can vary. • Polysaccharide: Glycan composed of repeating monosaccharides, generally greater than ten monosaccharide units in length.

  11. Monosaccharides 5-carbon and 6-carbon sugars predominate Chirality - optical active centers

  12. Common Monosaccharides Neutral Sugars Amino Sugars Acidic Sugars

  13. Monosaccharides - the basic structural unit • Carbonyl group at the end of the carbon chain (aldoses) or at an inner carbon (ketoses) has potential reducing power - the reducing terminus • The ring form of a monosaccharide generates a chiral (anomeric) center (at C-1 for aldo sugars or at C-2 for keto sugars).

  14. Oligosaccharides and Polysaccharides a-linkage b-linkage Glycosidic linkage can be a or b The convention is to draw the reducing end to the right. The terms “upstream” and “downstream” are sometimes used.

  15. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  16. To simplify the structural complexity of glycans, we will generally use a standard set of symbols to represent sugars. Symbolic Representation of Common Monosaccharides

  17. 6 S 6 S 6 S 6 S 6 S 6 S N S 2 S N S 2 S N S 2 S N S N S N S 2 S N S 3 S Saccharide Modifications increase the diversity and functionality of glycans Ac = O-acetyl P = Phosphate S = O-Sulfate NS = N-Sulfate NH2 = free amino group

  18. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  19. Glycoconjugates • Glycoconjugate: A compound in which one or more glycans (the glycone) are covalently linked to a non-carbohydrate moiety (the aglycone). • Glycoproteins: A protein with one or more covalently bound glycans. • Glycolipids: A molecule containing a saccharide linked to a lipid. • Proteoglycans: Any glycoprotein with one or more covalently attached glycosaminoglycan chains. Schematic representation of the Thy-1 glycoprotein

  20. Major Classes of Animal Glyconconjugates

  21. Symbolic Representation Full Traditional Simplified Traditional Symbolic Representation of Oligosaccharides

  22. Clustered O-linked Oligosaccharides • Electron micrograph of a cartilage proteoglycan shows the classical “bottle-brush” appearance • Many mucins contain clustered O-GalNAc linked oligosaccharides • These highly hydrated conjugates fill space, provide lubrication, and create clustered glycan ligands for binding receptors

  23. Lecture 1 - Key Points What is Glycobiology? Central Dogma Basic definitions Monosaccharides - the structural units of glycans Oligoaccharides consist of monosaccharides linked together Nomenclature and symbolic representations Major classes of glycoconjugates and oligosaccharides Clustered oligosaccharides Proteins can bind at either the ends of glycans or within the chains

  24. GLYCOSPHINGOLIPID Several Glycans Contain Terminal Sialic Acids = Sialic acid N-LINKED CHAIN O-LINKED CHAIN S O N Ser/Thr Asn OUTSIDE INSIDE CELL MEMBRANE

  25. Glycosaminoglycan Chains Contain Multiple Protein Binding Sites FGF-1 Antithrombin • Proteins can bind at the ends of N-linked and O-linked chains, and typically have binding pockets • Other proteins bind to internal sugar sequences, and have binding clefts • Valency is a major factor in determining overall affinity

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